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\begin{document}

\title{Effect of antenatal corticosteroids in late preterm delivery on neonatal
morbidity: A Randomised Controlled Trial}



\author[1]{Anisah Yahya}%
\author[1]{Hajaratu Sulayman}%
\author[1]{Isa Abdulkadir}%
\author[2]{Lawal Bola}%
\affil[1]{Ahmadu Bello University Teaching Hospital}%
\affil[2]{Ahmadu Bello University}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: The use of antenatal corticosteroids beyond 34 weeks of
gestation remains a debate. This study sought to determine the effect of
use of antenatal corticosteroids in late preterm delivery on neonatal
morbidity. Design: It was a randomized double-blind placebo and active
controlled multi arm trial. There were two study groups and one control
group. Setting: It was conducted at the department of Obstetrics and
Gynaecology and the Department of Paediatrics of Ahmadu Bello University
Teaching Hospital Zaria. Population: Pregnant women at 34 weeks 0 days
to 36 weeks 6 days of gestation scheduled for elective/emergency
delivery were recruited for the study. Methods: The study groups had
dexamethasone and betamethasone respectively while the control group had
a placebo. Main outcome: The primary outcome was incidence of
respiratory distress syndrome. Results: A total of 138 mothers and 146
preterm neonates were included in the study with 48 exposed to placebo,
49 exposed to betamethasone and 49 exposed to dexamethasone. A pairwise
analysis was done to test for difference between the groups. There was
no statistically significant difference in the incidence of respiratory
distress syndrome between the dexamethasone vs placebo (p= 0.98, RR 1,
CI 0.06-16.89), betamethasone vs placebo (p= 0.98 RR 1, CI 0.09-11.55)
and dexamethasone vs betamethasone (p=0.32, RR 0.5, CI 0.09-2.42)
Conclusion: Antenatal corticosteroids may decrease the need for neonatal
resuscitation at birth in late preterm neonates.%
\end{abstract}%



\sloppy


TITLE PAGE

Title: Effect of antenatal corticosteroids in late preterm delivery on
neonatal morbidity: A Randomised Controlled Trial

Authors

\begin{enumerate}
\tightlist
\item
  Anisah Yahya. Department of Obstetrics and Gynecology, College of
  Medical Sciences, Ahmadu Bello University/Ahmadu Bello University
  Teaching Hospital, Zaria, Nigeria.
\item
  Hajaratu Umar Sulayman. Department of Obstetrics and Gynecology,
  College of Medical Sciences, Ahmadu Bello University/Ahmadu Bello
  University Teaching Hospital, Zaria, Nigeria.
\item
  Isa Abdulkadir. Department of Paediatrics, College of Medical
  Sciences, Ahmadu Bello University/Ahmadu Bello University Teaching
  Hospital, Zaria, Nigeria.
\item
  Bola Biliaminu Lawal. Department of Community Medicine, College of
  Medical Sciences, Ahmadu Bello University Zaria, Nigeria.
\end{enumerate}

Corresponding author

Anisah Yahya. Department of Obstetrics and Gynecology, College of
Medical Sciences, Ahmadu Bello University/Ahmadu Bello University
Teaching Hospital, Zaria, Nigeria

+2348035925175, anisahy@yahoo.com, anisahungogo@gmail.com
ayahya@abu.edu.ng

Running title: Antenatal corticosteroids in late preterm delivery

ABSTRACT

Objective: The use of antenatal corticosteroids beyond 34 weeks of
gestation remains a debate. This study sought to determine the effect of
use of antenatal corticosteroids in late preterm delivery on neonatal
morbidity.

Design: It was a randomized double-blind placebo and active controlled
multi arm trial. There were two study groups and one control group.

Setting: It was conducted at the department of Obstetrics and
Gynaecology and the Department of Paediatrics of Ahmadu Bello University
Teaching Hospital Zaria.

Population: Pregnant women at 34 weeks 0 days to 36 weeks 6 days of
gestation scheduled for elective/emergency delivery were recruited for
the study.

Methods: The study groups had dexamethasone and betamethasone
respectively while the control group had a placebo.

Main outcome: The primary outcome was incidence of respiratory distress
syndrome.

Results: A total of 138 mothers and 146 preterm neonates were included
in the study with 48 exposed to placebo, 49 exposed to betamethasone and
49 exposed to dexamethasone. A pairwise analysis was done to test for
difference between the groups. There was no statistically significant
difference in the incidence of respiratory distress syndrome between the
dexamethasone vs placebo (p= 0.98, RR 1, CI 0.06-16.89), betamethasone
vs placebo (p= 0.98 RR 1, CI 0.09-11.55) and dexamethasone vs
betamethasone (p=0.32, RR 0.5, CI 0.09-2.42)

Conclusion: Antenatal corticosteroids may decrease the need for neonatal
resuscitation at birth in late preterm neonates.

Funding: The research was funded by Tertiary Education Trust Fund
(TETFUND) of Nigeria.

Trial registration: ClinicalTrial.gov, NCT03446937

Keywords: Antenatal corticosteroids, late preterm delivery, neonatal
morbidity.

INTRODUCTION

Preterm birth is a significant cause of neonatal morbidity and
mortality. The use of antenatal corticosteroids before 34 weeks of
gestation has been proven to prevent respiratory distress syndrome and
other morbidities in neonates.(1) However, limited evidence is available
for its use in the late preterm period.(2),(3)

Respiratory distress syndrome is one of the most important causes of
neonatal morbidity and mortality in preterm births. Other causes of
neonatal morbidity and mortality in preterm neonates include
intraventricular haemorrhage, sepsis, periventricular leucomalacia and
necrotizing enterocolitis. In preterm neonates, surfactant
insufficiency, immaturity and poor lung development result in
respiratory distress in preterm infants. As gestation advances, chances
of survival improve due to increasing maturity of the respiratory
system. Black neonates are said to have lower rates of respiratory
distress syndrome compared to non-black neonates.(4) This has been
attributed to qualitative difference in the surfactants and possible
anatomical difference in fetal lung development.(4) Despite this, there
is some evidence that infant mortality due to respiratory distress may
actually be affected by genetics race and ethnicity.(5)

Even though adequate fetal lung maturation for survival is expected to
be achieved by 34 weeks of gestation, neonatal and childhood
complications are still common in preterm neonates delivered after 34
weeks of gestation when compared to those delivered at term. (5),(6),
(7). This led to the recommendation by National Institute Of Child
Health And Human Development during a workshop in 2005 to direct
research to evaluate infants who are born between 34 and 36 weeks
gestation especially with regards to the benefits of use of antenatal
corticosteroids in the population. (8)

This study sought to determine the effect of antenatal corticosteroids
on neonatal respiratory distress syndrome and other neonatal
complications in women at risk of late preterm delivery in our clinical
setting.

METHODS

\textbf{Trial Design}

The study was a randomized double-blind placebo and active controlled
multi arm trial. Pregnant women at risk of late preterm delivery or
scheduled for delivery in the late preterm period were categorized into
three groups. There were two study groups and one control group.

\textbf{Participants}

Pregnant women at 34 weeks 0 days to 36 weeks 6 days of gestation and a
probability of delivery in the late preterm period irrespective of
diagnosis were recruited for the study. Also, pregnant women scheduled
for elective/emergency delivery in the late preterm period irrespective
of indication and route of delivery were recruited.

The study was conducted between February 2018 and May 2019 at the
department of Obstetrics and Gynecology and department of Paediatrics
Ahmadu Bello University Teaching Hospital, Shika. Recruitment was
stopped when desired sample size was achieved.

Gestational age was calculated from the date of last menstrual period or
early scan (before 20

weeks of gestation).

Probability of delivery is defined as:

Uterine contractions and cervical effacement of [?] 80\%

Preterm labor: Uterine contractions and cervical dilatation of 3cm.

Premature rupture of membranes: Evidence of liquor drainage by the
bedside.

\textbf{Intervention}

The first study group received antenatal corticosteroids in the form of
intramuscular dexamethasone sodium phosphate (produced by Taizhou
Overseas International Ltd. 126-128 Qingnian Road Jiaojiang, Taizhou,

Zhejiang, China).

The second study group received antenatal corticosteroids in the form of
intramuscular betamethasone sodium phosphate (USP 12601, CAT No 1068004,
Lot: R004E0, Twin brook Pkwy, Rockville MD, +1-301-881-0666, Singapore)

The control group received intramuscular water for injection as placebo
(Produced by Juhel pharmaceutical limited, Nigeria).

\textbf{Outcome measures}

Primary outcome measure:

Respiratory Distress:

(a)Tachypnoea with grunting, recession, or nasal flaring with diffuse
reticulogranular infiltrate on X-ray.

(b) Respiratory distress requiring the need for respiratory support by
72 hours of age and will consist of one or more of the following:

Requirement for intranasal oxygen for [?] 4 hours

Requirement for Bubble Continuous Positive Airway Pressure.

Secondary outcome measures:

1. Transient tachypnoea of the new born: Respiratory distress resolved
within 72 hours of

life without diffuse reticulogranular infiltrate.

2. Admission into Special Care Baby Unit (SCBU)/Neonatal Intensive Care
Unit (NICU):

Stay in the SCBU/NICU for more than 12 hours within the first 72 hours
of life excluding admission after discharge. Period of observation is
not considered as admission. (All preterm neonates are routinely taken
to the SCBU for observation immediately after delivery.)

3. Apnoea: an unexplained episode of cessation of breathing for 20
seconds or longer, or

a shorter respiratory pause associated with bradycardia, cyanosis,
pallor, and/or marked

hypotonia.

4. Need for resuscitation at birth: Failure of the new born to cry
and/or initiate spontaneous breathing at birth. To be determined by
skilled birth attendants that conducts the delivery.

5. Neonatal hypoglycaemia: Blood glucose level less than 2.2mmol/L at 3
hours after delivery.

6. Neonatal sepsis: Hypothermia or pyrexia and clinical evidence of
sepsis in any organ/system.

7. Neonatal death.

8. Maternal sepsis: Clinical evidence of endometritis characterized by
pyrexia [?] 38.0 sub-involution of uterus and foul-smelling lochia.

\textbf{Sample size}

The sample size for each group was determined by using the statistical
formula for comparison of proportions as follows:

n= 1/ ((1-f)) \selectlanguage{ngerman}× (2×\begin{CJK}{UTF8}{gbsn}〖\end{CJK}\selectlanguage{english}(Z\_\selectlanguage{greek}α\selectlanguage{english}+Z\_\selectlanguage{greek}β\selectlanguage{english})
\begin{CJK}{UTF8}{gbsn}〗\end{CJK}\selectlanguage{english}2\selectlanguage{ngerman}×P×(1-P))/\begin{CJK}{UTF8}{gbsn}〖\end{CJK}\selectlanguage{english}(P\_0-P\_1)\textsuperscript{2}

Where n = minimum sample size

Po = the proportion of participants in the control group that was
expected to develop respiratory

morbidity. In a study by Porto et al 23\% (0.23) was reported.

P1 = the proportion of participants in the experimental group that was
expected to exhibit the

outcome of interest which is respiratory morbidity. A reduction to 10\%
(0.10) will be

considered clinically significant in this study.

Z\selectlanguage{greek}α \selectlanguage{english}= was determined from a statistical table based on the value of the
level of significance. For

this study, it was set at 0.05. Therefore, Z\selectlanguage{greek}α\selectlanguage{english}= 1.96.

Z\selectlanguage{greek}β \selectlanguage{english}= was determined from a statistical table based on the acceptable
power of comparison

between 2 groups. For this study, power of 80\% (0.80) was used,
therefore Z\selectlanguage{greek}β\selectlanguage{english}= 0.84.

f = was the proportion of study participants who are expected to be lost
to follow up. For this

study f = 10\% (0.1)

n = 49.1

Each group was rounded up to 50.

\textbf{Randomization}

The WINPEPI version 11.65 software (75) was used to generate the table
of random numbers.

The table of random numbers was developed and kept with the research
unit of the pharmacy

department, Ahmadu Bello University Teaching Hospital, where the study
drugs were kept and dispensed for use once patients were recruited for
the study. The randomization code was only made available to the
principal investigator after completion of the trial for data analysis.

Patients that fulfilled the inclusion criteria were enrolled by the team
on call or managing team as they presented to the hospital. After
obtaining a written consent, the participants were requested to pick one
of the brown envelopes which contained the randomization number. A

proforma was then filled for the participants indicating the
randomization number. The randomization number was taken to the pharmacy
unit by the attending staff where the drugs were dispensed for
administration to the participants.

\textbf{Blinding}

All drugs were constituted and dispensed by a research assistant from
the research unit of the

pharmacy department of Ahmadu Bello University Teaching Hospital in
sterile syringes for immediate administration. All drugs were exactly
the same in appearance and volume. The principal investigator, research
assistants and special care baby unit/neonatal intensive care unit staff
were not aware of the group the women and neonates belonged to because
all drugs appeared exactly the same at point of administration.

\textbf{Statistical methods}

The data obtained was analysed using SPSS version 23.0. A pairwise
analysis (9) was done

to determine where the differences exist between the groups. Pairwise
analysis (betamethasone VS placebo, dexamethasone vs placebo,
betamethasone vs dexamethasone) was done for statistical analysis. The
socio-demographic characteristics, reproductive profile, and perinatal
characteristics of the women and their neonates in the group were
compared with students t-test for continuous variables and Pearson's Chi
Square (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}) test and Fisher's test for discrete
variables with normal distribution and Mann-Whitney U test for
continuous variables or those with non-normal distribution. P values for
all tests were two tailed and the level of significance was defined at
5\%. Relative risk with confidence interval was used to determine the
effects of corticosteroid treatment on perinatal and maternal outcomes.
Maternal and perinatal characteristics of the participants that were
statistically significant between the groups were subjected to logistic
regression to determine their effect on the statistically significant
outcome measures.

\textbf{Funding}

The study was funded by the tertiary education trust fund (TETFUND) of
the federal republic of Nigeria. However, the funding body did not
participate in the design, implementation and write up of the study.

RESULT

\textbf{Recruitment}

The study was conducted between February 2018 and May 2019. Recruitment
was stopped

when desired sample size was achieved.

During the period of study, a total of 150 pregnant women were
randomized for the study. Out of these women, 5 women carried their
pregnancies to term, 4 withdrew consent, 2 were discharged home and
subsequently lost to follow up and 1 had intrauterine fetal death. The
remaining 138 pregnant women were included in the study. Among these
women, there were 6 sets of twins and a set of triplets. This gave a
total number of 146 neonates in the study. Of these neonates, 48 were
exposed to antenatal placebo. 49 were exposed to antenatal betamethasone
and 49 were exposed to antenatal dexamethasone.

DISCUSSION

MAIN FINDINGS

The incidence of respiratory distress syndrome among late preterm
neonates in the placebo group, betamethasone group and dexamethasone
group were 2.1\%, 0\% and 2\% respectively. The incidence of respiratory
distress varies with race.(4) Low incidence of respiratory distress
syndrome have been reported among blacks.(4) and may explain the low
incidence of respiratory distress in our study coupled with the fact
that compared to other categories of preterm births, its incidence is
lower in late preterm neonates. There was no significant difference
between the group exposed to placebo versus antenatal betamethasone (p=
0.98, RR 1.0, CI 0.09-11.55), the group exposed to placebo versus
antenatal dexamethasone (p=0.98, RR=1.0, CI 0.06-16.87) and the group
exposed to antenatal betamethasone versus antenatal dexamethasone
(p=0.31, RR=0.5, CI 0.09-2.42). This is similar to the findings of Porto
et al(10) where he reported low incidence of respiratory distress among
late preterm neonates exposed to antenatal betamethasone and those
exposed to placebo (1.4\% and 0.8\% respectively) with no significant
difference in the incidence of respiratory distress between the 2
groups( p=0.54, RR 1.90). However, this is not consistent with the
findings of Balci et al(11) who reported an incidence of 16\% among late
preterm neonates that did not receive antenatal steroids and incidence
of 4\% among those that received betamethasone and the difference
between the two groups was statistically significant(p=0.046, OR 0.21).
The fact that Balci et al(11) found a significant difference in the
incidence of respiratory distress in their study may be due to the fact
that they did an open label trial which may have introduced some bias
unlike our study and that by Porto et al(10) which were both randomized
double blinded. Though a similar double blind randomized controlled
trial by Gyamfi-Bannerman et al(12) found a statistically significant
higher incidence of primary outcome in the late preterm neonates in the
control group, the primary outcome was a neonatal composite of treatment
including the use of CPAP or high flow nasal cannula at least for 2
hours, supplemental oxygen with a fraction of inspired oxygen of at
least 0.30 for at least 4 hours, extracorporeal membrane oxygen, or
mechanical ventilation or stillbirth or neonatal death rather than
respiratory distress alone. This may account for the difference in
findings.

The incidence of transient tachypnoea of the newborn was also low in
this study with one neonate (2.1\%) in the group exposed to placebo
developing the outcome (Tables 2 and 3). Our finding of low incidence in
transient tachypnoea was not consistent with other reports.
Gyamfi-Bannerman et al(12) reported an incidence of transient tachypnoea
of the newborn among late preterm neonates exposed to antenatal
betamethasone 6.7\% and 9.9\% in those exposed placebo (9.9\%) (p=0.002,
RR 0.68 CI 0.53-0.87). A higher incidence was reported by Porto et
al(10) where 24\% of late preterm neonates exposed to antenatal
betamethasone and 22\% of those exposed to placebo developed transient
tachypnoea. However, there was no significant difference between the
groups. The low incidence of transient tachypnoea of the newborn in our
study is in keeping with the low incidence of respiratory distress
syndrome noted in the study.

This study showed a statistically significant reduction in the need for
neonatal resuscitation at birth among the neonates exposed to antenatal
betamethasone compared to those exposed to placebo (p \textless{}0.001,
RR 7.0, CI 2.49-19.46) and also the neonates exposed to antenatal
dexamethasone compared to those exposed to placebo (p=0.010, RR 4.0, CI
1.86-26.03). This means that neonates born to women who received placebo
were 7 times more likely to need neonatal resuscitation at birth
compared to neonates born to women who received betamethasone and 4
times more likely to need resuscitation at birth compared to neonates
born to women who received dexamethasone. The use of betamethasone was
associated with a 40\% decrease in need for resuscitation at birth
compared to the use of dexamethasone though this was not statistically
significant (p=0.461).

A logistic regression analysis was done to determine the relationship
between the need for resuscitation at birth and the study group of the
women while adjusting for 1- and 5-minutes APGAR score that was
significantly higher in the betamethasone group when compared to the
placebo group. The result showed that after adjusting for 1- and
5-minute APGAR score there was a significant reduction in the likelihood
of need for neonatal resuscitation by about 85\% (ExpB=0.157, p=0.005)
when betamethasone was used compared to placebo.

Other studies have also reported decrease in the need for neonatal
resuscitation at birth in women exposed to antenatal corticosteroids
when compared with women exposed to placebo.(11),(12). This finding is
of significance especially in our environment where many deliveries are
conducted in the absence of skilled birth attendants that can adequately
offer neonatal resuscitation at birth.

The need for admission into SCBU was highest among the placebo group
(12.5\%), followed by the betamethasone group (8.2\%) and least in the
dexamethasone group (4.1\%). However, the differences observed were not
statistically significant (Tables 2, 3 and 4).

Apnoea was not reported in any of the study or control group. This may
be because continuous electronic recording of vital signs of the
neonates was not done in our study and apneic episodes are short in
duration. This has been observed in other studies where a lack of
correlation between nurses' records with continuous electronically
recorded events have been demonstrated (13),(14). In a randomized
controlled trial on the use of betamethasone for women at risk for late
preterm delivery, apnoea was reported to occur in 2.3\% of the group
that had betamethasone and in 2.6\% of the control group with no
significant difference between the two groups (p=0.57).(12) Other
studies on the use of antenatal corticosteroids in late preterm neonates
did not report on apnoea. (10),(11)

The neonates exposed to antenatal dexamethasone had the highest
incidence of hypoglycemia (14.3\%), followed by those exposed to
antenatal betamethasone (8.2\%). The neonates exposed to placebo had the
lowest incidence of hypoglycemia (4.2\%). However, the differences were
not statistically significant (Tables 2 ,3 and 4). Conflicting reports
exist in the literature with regards to incidence of hypoglycemia in
neonates following exposure to antenatal corticosteroids. While some
authors(12),(15) reported increase in the rate of hypoglycemia among
infants exposed to antenatal corticosteroids, others did not(6). A
systematic review and meta-analysis of randomized controlled trials on
the use of antenatal corticosteroids in near term and term fetuses also
showed an increased risk of neonatal hypoglycemia in women who received
antenatal corticosteroids at more than 34 weeks gestation.(15) However,
no adverse effects were reported in all the trials. This inconsistency
may be due to the fact that neonatal hypoglycemia is a common late term
neonatal complication irrespective of the use of antenatal
corticosteroids within the period.(16)

Incidence of neonatal and maternal sepsis were low and the differences
between the groups were not statistically significant. (Tables 2, 3 and
4). This is consistent with existing literature.(12)

STRENGTHS AND LIMITATIONS

The major strength of this study is the fact that it was a double blind
randomized controlled trial and both dexamethasone and betamethasone
were used as antenatal corticosteroids. However, it was conducted in a
single center which is a limitation.

CONCLUSION

This study found that the use of antenatal corticosteroids in late
preterm delivery did not have any significant effect on incidence of
respiratory distress syndrome and other neonatal morbidity but
significantly reduced the need neonatal resuscitation at birth.

RECOMMENDATIONS

In view of the findings in this study we recommend the use of antenatal
corticosteroids in women at risk of preterm delivery with the aim of
reducing the need for neonatal resuscitation at birth.

However, there is still the need for more trials on the effect of use of
antenatal corticosteroids in late preterm deliveries with the aim of
preventing neonatal morbidity and minimizing side effects on both mother
and neonates.

ACKNOWLEDGEMENT

We would like to acknowledge the staff of the labour ward and the
special care baby unit of Ahmadu Bello University Teaching Hospital for
their support during the period of the study.

DISCLOSURE OF INTEREST

The authors declare no conflict of interest. The authors do not have any
financial, personal, political, intellectual or religious
affiliations/relationships with any institution or organization that may
have influenced the research.

CONTRIBUTION TO AUTHORSHIP

AY was involved in the concept, design, definition of intellectual
content, literature search, data acquisition, data analysis, statistical
analysis, manuscript preparation, manuscript editing and manuscript
review. HUS and IA were involved in the definition of intellectual
content, data acquisition, manuscript editing and review. BBL was
involved in data analysis, statistical analysis, manuscript editing and
manuscript review.

DETAILS OF ETHICAL APPROVAL

Ethical approval to conduct the study was sought from the Health
Research and Ethics Committee of Ahmadu Bello University Teaching
Hospital Shika. The application was reviewed by the committee and
permission to conduct the study was given on 07/08/2017 with reference
number ABUTHZ/HREC/Y3/2017 (NHREC/10/12/2015; D-U-N-S-No 954524802;
ABUTH/HREC/CL/05/). The initial permission to conduct the study expired
on 07/08/2018 before the desired sample size was achieved. Permission
for extension of study period to 07/08/2018 was granted after due
process.

FUNDING

Funding was received from Institution Based Research funds of the
Tertiary Education Trust Fund of Nigeria. The funding is part of funding
for professional development and not for commercial or other purposes.

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